The objective of the proposed studies is to clarify the signaling events that are responsible for the failure of axon regeneration in the central nervous system (CNS), a phenomenon which leads to paralysis and a lack of functional recovery after spinal cord injury (SCI). Studies have shown that glial derived molecules such as myelin debris and chondroitin sulfate proteoglycans (CSPGs) comprise the major barrier to axon regeneration. Relatively little is known about how these molecules inhibit axon outgrowth after injury, however some studies suggest that they may signal through common mechanisms. Clearly there is a need to identify these convergent signaling "nodes" and to exploit them in the interest of developing novel therapeutics for SCI. To accomplish this goal, the proposed experiments will focus on identifying the mechanism of action of four novel compounds, identified in a high content chemical genetics screen, that have the ability to overcome both classes of glial derived inhibitors in cultured neurons. Excitingly, these four compounds not only have the ability to lend insight into the complicated signaling pathways involved in regeneration inhibition, but will also be tested in animal models of CNS regenerative failure in order to determine their potential to be used as treatments for SCI. This research will allow us to understand why neural connections are unable regrow and reform after traumatic spinal cord injury, thus providing a basis for the development of targeted treatment strategies for paralysis. Not only will these studies lead to a greater intellectual understanding of the mechanisms underlying the failure of neuronal regeneration, but may also directly lead to the development of a novel therapeutic for SCI, which has shown promise in preliminary studies.